脱质子化
钥匙(锁)
过程(计算)
工艺工程
流动化学
过程开发
流量(数学)
化学
计算机科学
制造工程
有机化学
工程类
操作系统
催化作用
物理
机械
离子
作者
Douglas A. L. Otte,Reed T. Larson,Embarek Alwedi,Travis J. Armiger,Qinghao Chen,Cheol K. Chung,James Corry,Richard Desmond,Patrick S. Fier,Robert D. Franklin,Erik D. Guetschow,Jackson R. Hall,Holst M. Halsey,Clara Hartmanshenn,Lisa Jellett,Nadine Kuhl,François Lévesque,Jonathan P. McMullen,Pratiq A. Patel,Mellie June Paulines
标识
DOI:10.1021/acs.oprd.3c00510
摘要
Nemtabrutinib (MK-1026) is a novel oral Bruton's tyrosine kinase (BTK) inhibitor for treatment of B-cell cancers. An initial synthetic supply route to generate ketone 3 relied on the generation of a highly reactive transient intermediate and the use of n-butyllithium. Cryogenic temperatures (−60 °C) were also required to achieve a modest 61% yield, with one major impurity, resulting from dehalogenation, accounting for the majority of the mass balance. An alternative process was developed to increase the yield and decrease the dependence on cryogenic temperatures, and this advancement was critical to the long-term robustness of the commercial process. Key advancements included performing the requisite deprotonation and metalation steps sequentially and performing the metalation and quench steps in flow. The final flow process was rapidly scaled from grams to tens of kilograms and has been successfully executed in a production facility.
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